Incidence and pre/post-treatment risk factors of glaucoma in Vogt-Koyanagi-Harada disease

To investigate the incidence and pre/post-treatment risk factors of glaucoma in patients with Vogt-Koyanagi-Harada (VKH) disease. Data regarding secondary glaucoma were collected from the medical records of patients with VKH disease who were followed up at the uveitis service at Hiroshima University for more than 6 months. We examined the incidence of glaucoma and pre/post-treatment risk factors for glaucoma in patients with VKH disease. Forty-nine patients with VKH disease were included in this study (31 women and 18 men). The mean age at onset was 50.4 ± 15.4 years and the mean length of follow-up was 40.7 ± 25.5 months. The most common initial treatment was pulse intravenous corticosteroid therapy (89.8%). Fifteen patients developed secondary glaucoma during follow-up. The median time of glaucoma onset from VKH development was 4.5 months (range 0–44 months). Disc swelling type as a pre-treatment factor (p = 0.089, hazard ratio = 7.268), worse final best corrected visual acuity (p = 0.099, odds ratio = 1.545), and cataract progression (p = 0.076, odds ratio = 7.886) as post-treatment factors showed trends for glaucoma development. The patients who progressed to the chronic recurrent stage had more complications including glaucoma. Secondary glaucoma occurred in more than 30% of patients with VKH disease. The factors that showed a trend toward glaucoma development may reflect an association with delayed treatment initiation and prolonged ocular inflammation.

melanocytes; it is characterized by bilateral panuveitis or posterior uveitis with exudative retinal detachment that may be associated with poliosis, vitiligo, alopecia, central nervous system manifestations, and inner ear symptoms [1][2][3]. High-dose oral or pulse intravenous corticosteroid therapy, followed by oral corticosteroid tapering over 6 months, is a common initial treatment. Progression to chronic recurrent disease occurs in patients with insufficient treatment; this stage is characterized by symptoms of depigmentation (e.g., choroidal depigmentation, known as "sunset glow" fundus), chronic anterior uveitis, and increased risks of ocular complications [1,[4][5][6][7][8][9][10]. To prevent development of the chronic recurrent stage, early administration of additional steroid-sparing immunosuppressive therapy within 2-3 weeks of onset has been recommended [11]. Complications of VKH disease include cataracts, glaucoma, choroidal neovascular membrane, and subretinal fibrosis; glaucoma is one of the most destructive complications because it causes irreversible visual field defects and visual acuity loss [12,13]. Patients with VKH disease have multiple risk factors for increased intraocular pressure (IOP), such as long-term corticosteroid treatment, posterior and anterior synechiae, and prolonged anterior chamber inflammation [13,14]. According to previous reports, the prevalence of glaucoma development in VKH disease is 15.8%-62.0% [13,[15][16][17][18] and there are several factors associated with ocular hypertension and glaucoma development, such as worse initial and final visual acuities, longer interval from onset to treatment initiation, more recurrent episodes, presence of posterior synechia / peripheral anterior synechiae, and the presence of uveal effusion [10,15,16]. These previous reports have assessed the risk factors of glaucoma development in VKH disease without distinguishing between pre-and post-treatment factors. We believe that evaluation of pre/post-treatment risk factors is of considerable importance to developing a treatment strategy for avoiding glaucoma development in VKH disease. In this study, we examined the incidence of glaucoma and pre/post-treatment risk factors for glaucoma in patients with VKH disease.

Study population
This single center retrospective study included patients with VKH disease who were treated at Hiroshima University from February 2015 to September 2019. The study protocol was approved by the University of Hiroshima Institutional Review Board, and required informed consent was waivered because of retrospective design.

Objectives
The primary objectives were to investigate the incidence of glaucoma and pre/post-treatment risk factors for glaucoma in patients with VKH disease. The secondary objectives were to analyze the factors associated with chronic recurrent progression and to explore the mechanisms underlying glaucoma development in patients with VKH disease.

Data collection
VKH disease was diagnosed in accordance with international diagnostic criteria [19]. A complete uveitis workup was performed for each patient to exclude other causes of uveitis. No patients had systemic symptoms related to tuberculosis and all chest radiographs were normal. The results of an interferon-gamma release assay for tuberculosis and the rapid plasma reagin test and anti-Treponema pallidum antibody assay for syphilis were negative. Patients were excluded from the study if they had less than 6 months of follow-up, were diagnosed with glaucoma before the onset of VKH disease, and/or were unable to undergo a fundus examination. VKH disease is categorized into two different clinical stages: acute VKH disease (acute uveitis with diffuse granulomatous choroiditis, secondary exudative retinal detachment, and optic disc hyperemia and disc swelling) and chronic recurrent VKH disease (recurrent granulomatous anterior segment inflammation with sunset glow fundus) [10,20]. The type of VKH disease in the acute stage was classified as the disc swelling type or the serous retinal detachment (SRD) type according to clinical findings as described in a previous report [21].
Patients with acute VKH disease were initially treated with oral corticosteroid or intravenous pulse therapy (1000 mg methylprednisolone per day for 3 consecutive days) followed by tapering of the oral corticosteroids. Topical treatments were used if necessary. Immunomodulatory therapy was administered if patients had a relapse or could not tolerate steroid therapy. Inflammatory relapse was defined as the presence of the following: anterior chamber cell grade ≥ 1 + cells according to the Standardization of Uveitis Nomenclature guideline [22], increase in subfoveal choroidal thickness or choroidal folding based on enhanced depth imaging optical coherence tomography, and indocyanine green angiography signs (e.g., choroiditis and hypofluorescent dark dots representing choroidal granulomas).
We recorded each patient's age at diagnosis of VKH, sex, length of follow-up, best-corrected visual acuity (BCVA), IOP, clinical type of VKH disease, interval from onset to treatment initiation, time from onset of VKH to glaucoma development, clinical findings, treatment, total dose of corticosteroids, and complications (e.g., cataract progression, subretinal fibrosis, or choroidal neovascular membrane). Corticosteroid dose was provided as prednisolone equivalent. The following data were collected: fundus photography, optical coherence tomography, and visual field examination findings. Glaucoma was diagnosed in eyes with glaucomatous optic disc damage (thinning of the neuroretinal rim, notching, or a defect in the retinal nerve fiber layer) or glaucomatous visual field loss, and sustained elevation of IOP (> 21 mmHg) requiring medical and/or surgical treatment [18,22]. Glaucomatous visual field loss was defined as the presence of any of following criteria according to the Humphrey visual field analyzer: (1) in the pattern deviation probability plot, there were three or more points with p value < 5% adjacent to each other except for the most peripheral inspection points, and the p value of one of the points located was p < 1%, or (2) the glaucoma hemifield test was out of the normal range. Persistent anterior uveitis was defined as the presence of anterior chamber cell grade ≥ 1 + cells (according to the Standardization of Uveitis Nomenclature guideline) for more than 6 months [22]. Sunset glow fundus was defined as orange-red discoloration in funduscopic images caused by inflammation-related choroidal depigmentation after the onset of VKH disease. Cataract progression was defined as the progression of lens opacity from a baseline status of mild or no cataract to a grade of clinically significant cataract requiring cataract surgery.

Statistical analyses
All statistical analyses were conducted using JMP software version Pro 16 and SAS version 9.4 (SAS Inc., Cary, NC, USA). Clinical characteristics were compared between the groups with and without glaucoma, and with and without progression to the chronic recurrent stage. For continuous variables, a two-factor nested random effects model with JMP software was used. For categorical variables, comparisons by person were analyzed with the chi-squared test with JMP software, and comparisons by case were analyzed with the mixed-effects logistic regression model with SAS. Kaplan-Meier survival curves were used to depict glaucoma development during follow-up. A frailty model with SAS was used to identify factors predictive of glaucoma in the pretreatment findings. Independent variables were age at onset, initial BCVA (logarithm of the minimum of angle resolution [logMAR]), interval from onset to treatment initiation, and type of VKH disease (disc swelling type or SRD type). A mixed-effects logistic regression model with SAS was used to identify posttreatment factors associated with secondary glaucoma development. Independent variables were final BCVA (logarithm of the minimum of angle resolution [logMAR]), use of pulse intravenous corticosteroid therapy, total corticosteroid dose, use of immunosuppressive therapy in the chronic stage, clinical findings (i.e., persistent anterior uveitis, sunset glow fundus, peripapillary atrophy, posterior synechiae, and peripheral anterior synechiae), and complications of VKH disease (i.e., cataract progression and subretinal fibrosis). Variables having a significant univariate test were selected as candidates for the multivariate analysis. Continuous data are presented as means ± standard error. P-values < 0.05 were considered indicative of statistical significance.

Results
Forty-nine patients (31 women and 18 men) with VKH disease were included in this study. Patient characteristics are summarized in Table 1. The mean age at onset was 50.4 ± 15.4 years; the mean length of follow-up was 40.7 ± 25.5 months. One eye with bullous keratopathy was excluded because of an unobservable fundus; thus, 97 eyes were included in the analyses. No patient had a history of glaucoma before the onset of VKH disease. Pulse intravenous corticosteroid therapy was administered as initial treatment in 89.8% of patients. For the rest of the patients, oral systemic corticosteroid (0.5 mg/kg of oral prednisolone) was administered for one patient, and two patients in the chronic stage in whom systemic steroids were contraindicated, received cyclosporine as initial treatment. Two were treated with local administration of corticosteroids because they refused systemic treatment. Immunosuppressive therapy was introduced in 44.9% of all patients.
Fifteen out of 49 patients developed glaucoma as a complication (30.6%). Glaucoma was diagnosed bilaterally in all 15 patients (n = 15, 30.9%); while all 30 eyes showed glaucomatous disc damage, glaucomatous visual field defects were present in 23 of the 30 eyes (76.7%). The median time from onset of VKH to the development of glaucoma was 4.5 months (range 0-44 months). The follow-up period for patients with glaucoma was longer than that of patients without glaucoma (p = 0.0003). Patients with glaucoma also had worse final BCVA (p = 0.0003), and a higher incidence of progression to the chronic recurrent stage (p = 0.042). They were treated with a higher dose of total corticosteroid (p = 0.046). Complications of VKH disease such as cataracts (p = 0.003) and subretinal fibrosis (p = 0.011) were also more prevalent in patients with glaucoma. Kaplan-Meier survival curve analysis showed that glaucoma occurred in 19.8% of patients at 4 months and 26.6% at 13 months of follow-up, respectively (Fig. 1).
The frailty model analysis to evaluate pre-treatment risk factors showed that patients with the disc swelling type in the acute stage were more likely to develop glaucoma than those with the SRD type, although the difference was not statistically significant (p = 0.089) ( Table 2). Compared with patients with the SRD type, the mean age at onset was older (47.5 ± 1.9 vs 55.5 ± 0.4 years, p = 0.0001) and the interval from onset to treatment initiation was longer (2.2 ± 1.0 vs 8.6 ± 1.4 weeks, p = 0.0003) in the disc swelling type. The mixed-effects logistic regression model analysis to evaluate post-treatment risk factors revealed that worse final BCVA (p = 0.024), sunset glow fundus (p = 0.047), cataract progression (p = 0.004), and subretinal fibrosis (p = 0.008) were statistically significant for glaucoma development in VKH disease in the univariate analysis (Table 3). In contrast, according to multivariate analysis, none of these factors were statistically significant for glaucoma development in patients with VKH disease. However, cataract progression (p = 0.076) and worse final BCVA (p = 0.099) showed trend for glaucoma development. Table 4 shows the characteristics of patients with and without chronic recurrent progression. Patients who progressed to chronic recurrent VKH disease developed glaucoma (p = 0.047), cataract progression (p = 0.014), and peripapillary atrophy (p = 0.006) more frequently than those without chronic recurrent progression.
The mechanisms underlying glaucoma development in patients with VKH disease are summarized in Table 5. Two patients (four eyes) developed acute angle-closure glaucoma because of ciliary body detachment at the onset of disease; the remaining 13 patients (26 eyes) developed glaucoma in the chronic stage. Among these 30 eyes with glaucoma, peripheral anterior synechiae were observed in 40% and steroid-induced IOP elevation was observed in 53.4%.
IOP was normalized in 22 eyes with the use of IOP-lowering eye drops. Glaucoma surgeries were performed in eight eyes (30.8%); the most common glaucoma surgery was trabeculectomy (six eyes), followed by trabeculotomy (four eyes), and Ahmed glaucoma valve implant surgery (one eye). Multiple glaucoma surgeries were performed in three eyes.

Discussion
Glaucoma is a vision-threatening complication of VKH disease [12,14]. In this study, approximately one-third of patients with VKH disease developed glaucoma during follow-up, most commonly in relation to steroid treatment. The disc swelling type in the acute stage as a pre-treatment factor approached significance for glaucoma development. Worse final BCVA and cataract progression as post-treatment factors may be associated with glaucoma development.
The prevalence of glaucoma in patients with VKH disease has been previously reported (15.8%-62.0%); however, the definition of this glaucoma has been inconsistent [13,[15][16][17][18]. According to the definition of glaucoma (IOP elevation > 21 mmHg, and glaucomatous visual field loss or glaucomatous disc damage) as previously reported by Foster et al. [18], more than 30% of patients developed glaucoma in this Table 1 Clinical characteristics of patients with Vogt-Koyanagi-Harada disease *p < 0.05, two-factor nested random effects model, **p < 0.05, chi-squared test, ***p < 0.05, mixed-effects logistic regression model a Data are expressed as mean ± standard error (range) BCVA best-corrected visual acuity, IOP intraocular pressure, logMAR logarithm of the minimum of angle resolution, NA not available study. There have been various hypotheses concerning the mechanism that underlies glaucoma development in patients with VKH disease [13,15,16,18].
In the present study, while the rate of acute angle-closure glaucoma in this study was low (6.7%), common causes of glaucoma development were peripheral anterior synechiae and steroid-induced IOP elevation in the chronic stage. which was comparable with the rate in a previous report [16].
According to the largest prospective study, the following were the risk factors for glaucoma in patients with VKH: worse initial and final visual acuities, longer interval from onset to treatment initiation, more recurrent episodes, and posterior synechiae [13]. Other reports showed that the formation of peripheral anterior synechiae, the presence of uveal effusion, and a greater frequency of recurrent inflammation were associated with ocular hypertension and glaucoma [15,16]. In our study, pre-treatment factors for glaucoma development were not evident, but the patients with the disc swelling type had a tendency to develop glaucoma. Worse final BCVA, cataract progression, and subretinal fibrosis were the post-treatment factors associated with glaucoma development in univariate analysis; the significance of these factors were however not evident in the multivariate analysis.  The disc swelling type in our study had a longer interval until treatment initiation, which was consistent with previous studies; this is due to the milder visual disturbance and the atypical presentation in the eyes with the disc swelling type than those with evident SRD type, which may delay diagnosis and treatment  [8,23]. Our results also showed that patients in the chronic recurrent stage had more complications, such as glaucoma, cataract progression, and subretinal fibrosis. Taken together, glaucoma was more likely to occur in patients who progressed to the chronic recurrent stage due to persistent ocular inflammation, and these patients were more likely to have more complications and consequently have worse BCVA.
There is increasing evidence that systemic corticosteroid therapy is not sufficient to prevent chronic inflammation [7,24,25]. Previous studies have shown that aggressive treatment with immunosuppressive therapy, such as mycophenolate mofetil combined with systemic corticosteroid therapy may prevent chronic inflammation in patients with early stage VKH disease, [24][25][26]. Combined steroid and non-steroid immunosuppression within the therapeutic window of opportunity (between 2 and 4 weeks after the onset of VKH disease) is crucial to prevent progression to the chronic stage [20,27]. Despite the introduction of immunosuppressive therapy, VKH disease may progress to the chronic recurrent stage if the initial treatment is delayed, requiring multiple immunosuppressive treatments to control ocular inflammation [28][29][30]. Our data also showed that a higher total corticosteroid dose and administration of immunosuppressive therapy did not suppress the development of glaucoma, suggesting that we might have missed the therapeutic window for some patients. Future studies should investigate the use of early immunosuppressive therapy in patients with VKH disease to prevent subsequent glaucoma development.
There were several limitations in this study. First, the number of patients was small because this was a single center study. In contrast with previous reports of patients who received high-dose oral corticosteroid therapy for initial treatment, most patients in the present study were those who received pulse intravenous corticosteroid therapy. Our study would have been strengthened by including multiple centers in Japan, where pulse intravenous corticosteroid therapy is generally used for initial treatment of VKH disease. One possible reason that some factors, such as the disc swelling type in the acute stage (in the frailty model analysis), worse final BCVA, cataract progression, and subretinal fibrosis (in the multivariate analysis), did not show statistical significance may be attributable to the lack of statistical power in our study. Second, although the mean ages at onset of VKH disease were similar in patients with and without glaucoma, our patient population may not have been homogenous in terms of lens opacity status. This aspect could have been addressed by including a larger number of patients who underwent detailed cataract assessment at disease onset. Lastly, some patients might have had undiagnosed glaucoma before the onset of VKH disease; the identification of a glaucomatous optic disc in such patients may have been hindered by optic disc swelling at the onset of VKH disease.
In conclusion, our findings suggest that disc swelling might be a pre-treatment risk factor for glaucoma development, while worse BCVA, cataract progression are presumable post-treatment risk factors. These factors may reflect an association with delayed initiation of therapy or the evolution of chronic recurrent stage. Early diagnosis, immediate commencement of therapy, and administration of immunosuppressive therapy combined with systemic corticosteroid therapy within the therapeutic window may prevent recurrent or persistent ocular inflammation, thus helping to prevent glaucoma in patients with VKH disease.